Because It’s All About Hormones, It’s All About Balance: Part 1

The Relationship Between Steroid Hormones, the Liver and Gut Health

Medically Reviewed by Dr. Emma Pollon-MacLeod, ND

The Relationship Between Steroid Hormones, the Liver and Gut Health

Hormones—The Body’s Key Regulators

The human endocrine system is a complex network of glands located throughout the body. These glands produce hormones which are chemical substances that govern various biological processes and are therefore critical to life. Hormones travel through the bloodstream to receptor sites located in various organs. Here, they initiate a specific response that is involved in creating internal balance within the body’s systems. This process is known as homeostasis, i.e., biological balance or equilibrium and hormones are the key regulators of it. Furthermore, the endocrine system intersects with both the central nervous system and digestive system, hence adding to its complexity and its diverse range of regulatory functions. From sleep to digestion to metabolism to immune function and the stress response, hormones are implicated in nearly every process within the body. As a result, there are different classes of hormones that do different things, but for the purpose of this article, we will be focusing on steroid hormones specifically.

Let’s Talk About Sex Hormones

Steroid hormones are made of cholesterol and are primarily formed in either the adrenal cortex, testes, or ovaries, and are also formed in the placenta during pregnancy. Cortisol is a glucocorticoid steroid hormone made in the adrenal cortex. It governs the stress response, influences energy levels and assists in metabolizing fats, proteins and carbohydrates and is involved in glucose metabolism. Progesterone, testosterone and estrogen are the main steroid sex hormones. They are produced mainly in the aforementioned reproductive organs and to a lesser extent in the adrenals. This hormonal trifecta is intricately connected and directly involved in reproduction. As such, they exist in different ratios within both natal sexes. In females, estrogen and progesterone are found in the highest concentration, while testosterone is found in the highest concentration in males. Because they are responsible for biological differentiation by way of secondary sex characteristics, they are often only associated with this biological mechanism or that of reproduction. However, their biological impact is multifaceted and far-reaching within the human body, yet many are unaware of the true impacts of sex hormones on our overall health.

Progesterone—The Park Ranger

Although progesterone plays a significant role in pregnancy, its main role is to oppose estrogen—it keeps it in check, which occurs in both natal sexes. Estrogen is responsible for the growth of cells, hence its role in reproduction. So, if progesterone is not around to keep it in check, cells would keep growing and certain diseases would take root. Moreover, progesterone is responsible for much more than reproduction which is why it is often referred to as a neurosteroid. That said, let’s get into the details of progesterone. It is required for the production of both cortisol and testosterone which makes it critically important in males and females alike. As such, I like to refer to it as “The Park Ranger” seeing it is like a nurturing caretaker whom all the forest’s critters and creatures rely on. It keeps the entire ecosystem in harmonious balance by ensuring nothing overgrows, and that everything is clean, pristine and nourished in order to function properly. Due to its neurosteroid effects, progesterone is closely tied to mood. Progesterone has been suggested to increase serotonergic neurotransmission via the regulation of the expression of serotonin-related genes and proteins. 1 It also helps keep us calm and achieve deeper sleep, seeing its by-product allopregnanolone acts upon the GABA receptors. GABA is the inhibitory neurotransmitter responsible for not only initiating alpha waves in the brain which keeps us calm, alert and focused, but can also assist in sleep. Furthermore, allopregnanolone has been shown toexert neuroprotective and restorative effects on traumatic and ischemic brain injuries where it appears to reduce edema and restore the function of the blood barrier. 2 Moreover, there is evidence that progesterone may slow down the progression of Alzheimer’s disease. Progesterone is also required for optimal thyroid function and is involved in effectively burning fat for energy. Lastly, it is required for bone synthesis so it aids in preventing osteoporosis and is also involved in insulin metabolism.

Testosterone—The Trainer

Testosterone is the hormone responsible for natal secondary sex characteristics and sperm production in males. It is also produced in females, but in much smaller amounts. Testosterone is responsible for maintaining lean muscle mass, a healthy glucose metabolism, cholesterol levels, and cardiovascular function. Needless to say, I like to refer to it as “The Trainer” because when it is balanced it keeps us in great shape! Testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. 3 It also plays a critical role in libido, bone density, memory, mood, and sleep quality. Lastly, testosterone is converted to estrogen making it equally important in both sexes.

Estrogen—The Efficiency Expert

Last, but not least, we have estrogen—it is produced mainly in the ovaries, adrenal glands and fat tissues. Again, both sexes have it, but females have the most. There are three types of estrogen: estrone (E1), estradiol (E2) and estriol (E3). E2 aka 17𝝱-estradiol is the most powerful and in the highest concentration and will be the focus for this article. Although recognized as the primary female sex hormone, the action of estrogen is not limited to reproductive tissues.4 Estrogen’s impacts are vast and multifaceted, a fact that many are unaware of. However, research is finally catching up and confirming how truly all-encompassing this powerful hormone really is. Estrogen receptor (ER𝝰 & ER𝝱) sites are found throughout the body and concentrated in unexpected locales, such as the brain and liver. As a result of this global expression, estrogen has been shown to influence a variety of physiological responses including neural development, cardiovascular health, and bone density. 4 Because it influences almost every tissue and organ, I like to refer to it as “The Efficiency Expert,” seeing when it is balanced, it really makes everything much more efficient which I will illustrate below.

Estrogen, Mood and Cognition

Like progesterone, estrogen is also considered a neurosteroid, because they both significantly influence GABA, dopamine and serotonin, further confirming their impacts on mood. Estrogen may produce its mentioned effects on cognition and mood especially through modulation of serotonergic function. Estrogen can increase serotonin (5-HT) levels and decrease 5-HT reuptake which allows 5-HT to remain longer in the synaptic cleft and exhibit prolonged effects on postsynaptic receptors. 1 Moreover, recent studies report on the interaction between estrogen and dopamine on cognitive domains, such as decision-making. 1 Estrogen and progesterone receptor sites are concentrated in the amygdala and hippocampus, further confirming their significant impacts on learning and memory.

Estrogen and Cardiovascular Health

Another incredible function of estrogen is keeping your cardiovascular system healthy and strong. It does this by regulating cholesterol and keeping your blood vessels relaxed and squeaky clean. Who would have thought, right?

Estrogen and Bone Health

Bones are actually living tissues that are constantly rebuilding themselves through a process called remodelling. Bones are continuously being broken down and then built up again. Remodelling is governed by cells known as osteoclasts and osteoblasts. The former break down bone, while the latter build it up. Estrogen appears to protect osteoblasts and slows down osteoclasts, which is why it is so important to bone health. It has also been demonstrated to prevent bone loss in males as well, again displaying how critically important it is to both sexes.

The Bi-Directional Relationship of the Liver and Steroid Hormones

The liver is the largest solid organ within the body. It is one of the most critical organs we have and works overtime to keep us alive and kicking. Its prefix is “live” alluding to the fact that without it we would well, not live. It is a remarkable organ that unfortunately takes a beating due to the unhealthy lifestyle factors that are associated with modern living. However, the liver is so remarkable that it can actually regenerate itself! Unfortunately, this phenomenon creates a catch 22 because its resiliency keeps the door open to a high degree of neglect, as it can take a heck of a lot before diseases take root. The liver’s main function is to metabolize every substance that enters your body. Along with cholesterol and glucose metabolism, the liver produces bile, which is stored in its best friend—the gallbladder. Bile is required for the break down of fats, protein and cholesterol in our diet. It also absorbs vitamins that are later stored in the liver along with minerals like copper and iron. Moreover, the liver is also responsible for the detoxification of drugs, alcohol, toxins and steroid hormones. It is a complex process, but simply put, the liver uses special enzymes to break down their structures so they can dissolve more easily and are excreted efficiently via the kidneys and bowels. This process is known as glucuronidation and the action of the enzymes is known as conjugation. The liver is also directly involved in the regulation of the immune system, seeing it has the highest concentration of specialized white blood cells called phagocytes in the body. Now that we have a basic understanding of the liver’s broad functions, let’s shift back to the topic at hand. As stated, the liver is responsible for hormone synthesis. Seeing the liver governs cholesterol metabolism, it is not surprising that hormone regulation is dependent on liver function. Firstly, a special liver enzyme called 5a-reductase 1 (5a-R1) regulates both testosterone and cortisol. Secondly, a highly specialized group of enzymes found primarily in the liver called cytochromes p450 (CYP) are involved in hormone synthesis and breakdown. CYP19 aka aromatase converts testosterone to estrogen. CYPs are also responsible for the removal of various compounds and assist in the detoxification of drugs. Thirdly, because steroids are made up of fat, they need to be bound to special glycoproteins that are produced in the liver. These glycoproteins carry the steroid hormones through the blood to their specific receptor sites and assist in hormone regulation. Lastly, because steroid hormone synthesis is dependent on healthy cholesterol metabolism, an impairment of any kind will directly impact how effectively these hormones can be made. For example, eighty percent of the circulating cortisol is synthesized mainly from the liver-secreted high-density lipoproteins (HDL) cholesterol. 5 So, if you don’t have adequate HDL levels, it will always be an uphill battle ensuring you have sufficient cortisol production. It is now clear how the liver impacts steroid hormones, but you might be asking yourself if steroid hormones impact liver function? They do indeed and there is emerging research that confirms this highly interwoven, bi-directional relationship is where “The Efficiency Expert” takes center stage.

Steroid Hormones and Liver Diseases

The liver houses a large number of estrogen receptors present within liver cells called hepatocytes which appear to protect against inflammation. Estrogen signaling facilitates the resolution of inflammation by inhibiting the production of pro-inflammatory cytokines, regulates apoptotic processes, and promotes liver cell regeneration; thus, limiting or preventing liver injury. 6 This function of estrogen is critical because factors such as hepatic inflammation, high sugar and fat intake, coupled with impaired glucose regulation and fatty acid metabolism drive conditions such as nonalcoholic fatty liver disease (NAFLD) and overall liver degeneration. Yep, you read that right, steroid hormones—particularly estrogen protect against the formation of degenerative liver diseases. There also appears to be a correlation between hormonal dysregulation and liver pathologies. The clearest example of this is the high prevalence of NAFLD in postmenopausal females. Alterations of the liver’s metabolic homeostasis are seen in conditions like polycystic ovarian syndrome (PCOS) and when testosterone is too low. The latter also has an increased risk of developing liver cancer. Although the focus for this article has been primarily sex steroids, there is also evidence correlating adrenal dysfunction to liver pathologies. NAFLD is seen in both high cortisol and aldosterone and can progress to life-threatening cirrhosis of the liver. Interestingly, the opposite has been documented wherein a clear link between cirrhosis and adrenal insufficiency (AI) has been seen. AI is a condition where the adrenals do not produce sufficient cortisol. In the context of cirrhosis it is likely due to insufficient cholesterol and inflammation, but also due to the involvement of an endotoxin known as lipopolysaccharides (LPS) which overstimulate and exhaust the HPA axis. They are able to do this because of their involvement in the Gut-Brain Axis. Activation of the HPA axis by stress leads to cortisol secretion. It can affect gut integrity, motility and mucus secretion, leading to changes of the composition of the gut microbiota. LPS on the surface of gram negative bacteria can affect the brain by mediating immune cells and vagus nerves. 7 When the body is under stress it will use progesterone and testosterone to make cortisol; thus, stress can not only affect gut health, it also drives hormonal imbalances. You can learn more about the Gut-Brain Axis here. This clearly elucidates how connected steroid hormones, liver function and the microbiome really are!

The Microbiome and Efficient Hormone Detoxification

Speaking of the microbiome, did you know that certain gut bacteria impact how efficiently hormones are detoxified and eliminated out of the body? Remember when I mentioned the liver uses enzymes to break down the steroid hormones via a process called conjugation? Well, certain strains of gut bacteria have the ability to reverse this process; therefore, the elimination of steroid hormones is impaired. Remarkably, these bacteria have an enzyme called 𝝱-glucuronidase which is actually able to deconjugate steroid hormones, thereby transforming them back to their original state. Crazy, right? The term used to describe which bacteria have high or low 𝝱-glucuronidase activity is referred to as the estrobolome and there is also evidence of a testrobolome. Upon first glance, this may appear to be a good thing; however, it is problematic, seeing the level of circulating hormones actually increases. Because the function of hormones is to establish and maintain homeostasis, it is all about balance when it comes to them. Like Goldilocks and her porridge, their concentrations need to be “just right,” not too high or low at any time. As such, when your body is still able to produce the right level of hormones based on your life phase and your gut bacteria are bringing the “dead” ones back to life, you are going to run into problems. Lastly, because steroid hormones are eliminated in bile, it too can get recycled in this process which is also a problem. Once bile enters the large intestine, it contains a lot of toxins and must leave your body never to return. What’s even more fascinating about this process is that it is not just harmful bacteria that are capable of this. There are multiple strains that classify as the estrobolome including beneficial bacteria, further confirming the importance of a balanced microbiome in the presence of optimal digestion. We wanna make sure that everything is not only metabolized correctly, but that everything we don’t want is eliminated as quickly as possible. This is why bowel regularity is key to health. With steroid hormones, the faster things move through your gut, the less time the estrobolome has to act on the conjugated hormones that are bound for excretion.

Supporting the Liver and Gut for Healthy Hormones

Now that we have clarity into the tri-directional nature of hormones, liver function and gut health, how can we best support these functions in order to maximize quality of life as we age? Because the gut is involved, the starting point is always diet. A whole food diet rich in fruits, vegetables, prebiotic fibres and resistant starch, with a low glycemic approach should always be your starting point. In short, cut out all of the processed, artificial junk and drink plenty of water. This will not only provide your body with vital nutrients, but feed beneficial gut bacteria and establish a healthy microbiome. Plus, a diet rich in fiber will keep things moving which is what we want! To learn more about the true power of fiber, check out one of our previous articles here. In terms of the liver, we all need to give it way more love! Good, solid nutrition is an excellent place to start, but the truth is your toxic load has to be lightened in order to truly give those hepatocytes the ability to regenerate. This means that alcohol consumption needs to be significantly reduced or eliminated along with any unnecessary exposure to toxins. Don’t forget, it is a biome disruptor, so on top of causing gut dysbiosis, it will damage your liver. That said, there are certain foods that can be easily added to your diet to improve liver function. One of my favourites is dandelion greens. These bitter greens are choke-full of vitamins and traditionally used as a liver and gallbladder tonic, seeing they stimulate bile flow. High-quality dandelion greens are more common at markets and grocers, so start adding them to your rotation of greens. They are bitter, but you’ll get used to them! They can be lightly sautéed with garlic, blended into a smoothie or taken as a tea if dried leaves are only available. Turmeric and ginger root are both powerful anti-inflammatories, but are also powerful digestive tonics that support liver and gallbladder function. The raw spice can be made into a tea or warm latte, where the fresh roots can be added to soups, curries, smoothies and fresh pressed juices. Citrus fruits are also a great addition when supporting liver and gallbladder function. Their high acid content will aid in digestion and assist with bile flow. The skins of citrus are also packed with the flavonoids quercetin, hesperadin, and naringin. The former optimizes liver function, while the latter pair have been shown to feed to the healthy bacteria in our gut. Add in raw citrus as snacks throughout the day or blend them up with ginger and turmeric root and make a pulpy juice. Don’t forget to eat the white bitter skin because that’s where all the flavonoids are! You can also find quercetin in onions where it is highly concentrated. Another consideration is N-Acetyl-L-cysteine (NAC). It is an amino acid that has a powerful action on liver function. It is a precursor to glutathione (GSH) which is one of the most important antioxidants in the body. GSH boosts detoxification of toxins and heavy metals, hence critical to optimal liver function. It has also been shown to protect the liver from drug toxicity. You can learn more about NAC here. L-glutamine is another highly beneficial amino acid that supports overall digestive function. It is the most abundant amino acid in the body; thus, has a myriad of actions. L-glutamine is another precursor to GSH and used to treat leaky gut because it supports gut barrier integrity. It is also a precursor to GABA, hence excellent for stress management and can aid in sleep. Learn more about the benefits of L-glutamine here. The above recommendations are excellent starting points to improve overall digestion and hormone health, but if you need some guidance consider working with our registered holistic nutritionist to get your diet cleaned up and gut reset. However, if you are ready to take your health to the next level, consider booking in with one of our team of experts for microbiome mapping and hormone balancing. *This article is not intended to represent medical advice. Please contact a qualified health practitioner if you want to use any natural health products for specific health conditions. Furthermore, please note that the terms “female” and “male” are strictly used to represent biology and in no way reflect one’s gender identity or expression.

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